This more advanced mouse model, to be jointly developed by USF and the University of Pennsylvania, may help explain the potential role that cellular immunity plays in fighting or promoting the devastating neurodegenerative disease.
"We want a more well-rounded, extensive understanding of the immunological responses to the Alzheimer's vaccine, particularly potential cellular immunity, to determine whether the responses are beneficial or not," Kenneth Ugen, PhD, associate professor of medical microbiology and immunology and principal investigator of the grant. "The research is important to the vaccine's future effectiveness and safety in humans."
The researchers will also work on developing a DNA vaccine against Alzheimer's disease, which may have technological or economical advantages over conventional vaccination methods.
This second National Institute on Aging grant is in addition to a $2.2-milliion NIA grant awarded last year to David Morgan, PhD, professor of pharmacology. Dr. Morgan heads the USF Alzheimer's vaccine research program, which includes Dr. Ugen as one of its major investigators. Dr. Morgan is a co-principal investigator on the new grant.
Earlier work by the USF group showed that an experimental vaccine prevented memory loss in mice with mutated human genes (known as transgenic mice) that produce age-related brain degeneration much like Alzheimer's disease. The study, published in the journal Nature, attracted international attention.
The new grant includes an outside scientist, internationally-recognized for vaccine development, who supplements Dr. Ugen's background in this area. This collaborator, co-principal investigator David Weiner, PhD, an associate professor of pathology at the University of Pennsylvania, pioneered an experimental DNA vaccine against HIV-1, the virus that causes AIDS. Dr. Ugen is a member of Dr. Weiner's multi-institutional team working on the genetic vaccine for HIV-1.
The researchers plan to cross two lines of transgenic mice to produce a new mouse model for Alzheimer's disease. Mice carrying the human genes for MHC I and MHC II (major histocompatibility molecules I and II), provided by Dr. Weiner's lab, will be mated with the transgenic Alzheimer's mice developed at USF. MHCI and MHCII, present on the surface of cells, are important in helping the body to recognize certain foreign substances, or antigens, as harmful. "The resulting offspring will be mice expected to respond to the anti-Alzheimer's vaccine with more human-like immune reactions," Dr. Ugen said.
The researchers will inject the mice bred to develop age-related neurodegeneration with the anti-Alzheimer's vaccine, which contains as its antigen a synthetic version of beta amyloid, the protein that builds up in the brains of Alzheimer's patients. Then, they will analyze the responses of immune cells to the vaccine. They will look for harmful side effects and, in particular, study the role of cellular immunity in any beneficial effects from the vaccine.
Vaccines traditionally protect against viruses or bacteria that invade the body from outside sources. The anti-Alzheimer's vaccine works by triggering the immune system to recognize beta amyloid — a protein made by the body — as a foreign invader and attack it.
"We're dealing here with the new use of a vaccine to fight a chronic neurodegenerative disease," said Dr. Morgan, a co-investigator for the study. "It is still unclear whether the cellular immune response to the vaccine is good or bad. In trying to provoke an immune response that prevents or removes the buildup of beta amyloid deposits in the brain, it may inadvertantly be creating other autoimmune reactions against nerve or muscle fibers that could be damaging."
Learning more about vaccine-induced immunity is expected to help researchers formulate a reliable vaccine that will work most safely and effectively for the large population of people at potential risk for Alzheimer's disease.